Unraveling the mysteries of Kawasaki disease using the genetics/genomics tool box


Fri Mar 18, 2011


Jane Burns
UCSD Division of Allergy and Immunology


Kawasaki Disease (DBP 1)





Kawasaki disease (KD) is a self-limited, acute vasculitis of unknown etiology that is the most common cause of acquired heart disease in children in Western developed countries and Asia. In the U.S., there are 5-6,000 new cases diagnosed each year. However without a specific diagnostic test, the true burden of disease is unknown. At Rady Children’s Hospital San Diego, we cared for over 90 new KD cases in 2010 and follow over 1,200 families in our outpatient KD Clinic (350 outpatient visits/yr.). In Japan, the country of highest incidence (>215/100,000 children < 5 yrs), there are more than 11,000 new cases each year and rates continue to rise. KD causes a vasculitis that damages the coronary arteries and other medium-sized muscular arteries AND also can cause an important myocarditis. Clearly, aneurysm prevention is a primary goal of treatment during the acute phase of the disease, which leads us to focus on CAA in this application. We conducted extensive transcriptome and genetic analyses, including genome-wide association studies (GWAS), in partnership with the International KD Genetics Consortium (IKDGC) and the Genome Institute of Singapore (GIS) using  >3,000 DNA samples from KD subjects and their families. We identified and validated polymorphisms in genes in immune response and TGFβ pathways that associate with KD susceptibility and disease outcome. These data underlie the current paradigm that KD is triggered by an infectious agent that elicits an acute inflammatory response in genetically susceptible children. Our preliminary studies also demonstrate that susceptibility to coronary artery aneurysms (CAA) the major complication of KD, and response to high dose intravenous immunoglobulin (IVIG), the major therapy to prevent CAA, are also under genetic control. Despite these significant genetic advances, the phenotypic correlates of these genetic variants remain unknown. Based on our genetic/genomic studies, we propose as a new paradigm that aneurysm syndromes including Marfan, Loewys-Deitz, and Job’s syndrome, share with KD a final common pathway of endothelial and epithelial to mesenchymal transition stimulated by TGFβ and resulting in myofibroblasts that migrate into the arterial wall, secrete factors that disrupt the extracellular matrix, and present antigen to T-cells that exacerbate the local inflammatory state. We further propose that an intersection of up-regulated signaling pathways involving chemokines and signaling through the calcineurin/NFAT pathway further contributes to vessel wall damage.



Dr. Jane C. Burns is a native of San Francisco, California. She received her M.D. degree at the University of North Carolina in Chapel Hill in 1978 and completed her pediatric residency and Chief Residency at the University of ColoradoSchool of Medicine in Denver, Colorado. In 1983, Dr. Burns moved to Harvard Medical School and the Boston Children’s Hospital for additional training in pediatric infectious diseases and molecular virology. She joined the faculty at Harvard in 1986 and in 1990 moved to San Diego, California, where she joined the faculty at the University of California as an Assistant Professor. Dr. Burns moved up through the ranks and was appointed Professor of Pediatrics in 1999. She was appointed Chief of the Division of Allergy, Immunology, and Rheumatology in 2000. Currently, Dr. Burns is Director of the Kawasaki Disease Research Center at UCSD/Rady Children’s Hospital where she leads a multidisciplinary team that cares for 80-90 new Kawasaki disease patients each year and follows over 1,200 families in the KD Clinic. Her passion for studies of Kawasaki disease has spanned almost three decades with her first publication on KD in 1982. In addition to her academic pursuits, Dr. Burns is the mother of two daughters. Her husband, John B. Gordon M.D., is an interventional cardiologist who cares for adults with long-term sequelae of KD. Together, Burns and Gordon with a team from UCSD have launched The Adult KD Collaborative, a long-range epidemiologic and clinical study of cardiovascular biomarkers and functional studies in adults who suffered from KD in childhood.


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